The broad goal of this revision supplement to AG 029573 "Neuroimmune Mechanisms of Depressive-Like Behavior during Aging" is to determine the efficacy of a moderate exercise training intervention in attenuating exaggerated behavioral disturbances induced by inflammation in aged mice. This proposed work adds significant translational aims to the prior funded grant and is novel and exciting because we will be testing a defined mechanism whereby exercise may be exerting its behavioral effects. Our preliminary data support our hypothesis that exercise will act in an anti-inflammatory capacity, specifically within visceral adipose tissue, resulting in a reduction in inflammation within brains of aged mice. This, in turn, will result in an attenuation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in the brain and leading to a decrease in behavioral disturbances including depressive-like and anhedonic behavior, fatigue, and fatigability. Our three objectives include examination of exercise efficacy in response to (1) an acute inflammatory stimuli (lipopolysaccharide;LPS), (2) a chronic inflammatory stimuli (Bacille Calmette-Guerin;BCG), and (3) intracerebroventricular LPS. In addition to behavior, we will also examine whether exercise reduces brain cytokines, IDO expression and activity and the kynurenine/tryptophan ratio in response to inflammation. We are making excellent progress on the original aims, and the proposed research fits well with the stated objectives of the parent grant because all of the behavioral and biochemical measurements outlined in the parent grant will be utilized in the proposed studies. There is very little technical risk in conducting these experiments, but there is real potential for these experiments to bear a high yield. We have initiated a collaboration with Dr. Jeffrey Woods who will assist in the design and conduct of the exercise intervention. If the hypotheses of this research are supported, these preclinical data will be used as support for future grant applications aimed at determining the effectiveness of regular exercise and the role of IDO in behavioral disturbances in aged persons with chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: The relevance of this proposed research lies in its potential to identify a safe, effective strategy to attenuate inflammation-induced behavioral disturbances (depression, mood disorders, fatigue) in older adults.